This invention relates to compositions comprising nicotine and methods for preparing said compositions being useful in drug therapy, preferably nicotine replacement, including tobacco substitution and smoking cessation.
Nicotine replacement therapy as a smoking cessation strategy has been successful in the past. Previous nicotine-containing compositions aiming towards the purpose of reducing nicotine craving for subjects wishing to stop their use of tobacco products include e.g. U.S. Pat. No. 3,845,217 disclosing chewable compositions, U.S. Pat. No. 4,579,858 disclosing high-viscous nicotine nose-drop compositions, U.S. Pat. No. 5,525,351 disclosing nicotine-containing saliva-soluble gels, U.S. Pat. No. 5,656,255 disclosing low-viscous nicotine-containing compositions suitable for nasal spray administration, U.S. Pat. Nos. 4,920,989 and 4,953,572 disclosing the use of inhalation aerosol, BP 1,528,391 and BP 2,030,862 disclosing liquid aerosol formulations adapted as mouth-sprays, and devices for transdermal delivery of nicotine.
A well-known side effect of nicotine is related to its concentration dependent local irritation. This adverse effect is particularly noticeable when nicotine formulations are applied topically, including the transmucosal, comprising buccal and nasal, and transdermal administration routes.
UK Patent application GB 2 230 439 A describes nicotine lozenges with a shell or coating containing an oral-acting local analgesic, preferably eugenol. Though not stated explicitly to be the cause of the so included local analgesic, the aforesaid disclosure is said to substantially ameliorate the sensation of burning in the mouth experienced with conventional nicotine lozenges. Similarly, nicotine-compositions formulated in lozenges containing local analgesic have been disclosed in AU 662877 in which the latter agent is said to temporarily interfere with taste receptors which is said to reduce the desire to eat.
The concentration of nicotine in several of the above mentioned inventions, and product designs thereof, is hence limited by adverse effects caused by or related to its local irritation.
Prior art describes other capsules, tablets, and lozenges for oral delivery of nicotine. For example, WO 88/03803 discloses a chewable capsule filled with a liquid containing 0.1-10.0 mg of nicotine, together with additives for improving flavor and dispersion. The capsules are provided in a variety of pH values to allow the patient a choice of nicotine absorption rates, and are especially intended as an aid to quit smoking.
Another nicotine capsule formulation is disclosed by Jarvik et al. (Clin. Pharm. Ther. 1970, 11, 574) for ingestion as a smoking cessation aid. The subjects, according to the theory that intestinal absorption of nicotine could produce significant blood levels, however, apparently swallowed these capsules whole. The study showed a small but significant decrease in the number of cigarettes smoked by subjects, but no quantitative measurements of nicotine blood levels were obtained.
BE 899037 discloses a tablet containing 0.1 to 5 mg nicotine as a base or water-soluble acid salt as an aid for quitting smoking.
Shaw (for example in GB 2 142 822 and U.S. Pat. No. 4,806,356) describes a nicotine lozenge prepared from a mixture of inert filler material, a binder, and either pure nicotine or a nicotine-containing substance by cold compression.
U.S. Pat. No. 5,512,306 discloses a nicotine product for oral delivery in the form of an inclusion complex of nicotine and a cyclodextrin compound. It also discusses the use of various excipients and direct compression for manufacture of the product.
WO 90/03776 discloses nicotine-containing tablets comprising more than 75% PEG. WHO has stated the acceptable daily intake (ADI) of PEG to be 10 mg/kg body weight. Using nicotine tablets according to WO 90/03776 in smoking cessation therapy would though result in an ADI of PEG much higher than 10 mg/kg body weight. Our present invention does not contain PEG at all.
WO 97/42941 discloses a slowly erodible nicotine lozenge that allows delivery to the buccal mucosa over an extended period of time.
The literature also describes different designs of tablets for delivering nicotine to the mouth and digestive system.
Wesnes and Warburton (Psychopharmacology 1984, 82, 147; ibid. 1986, 89, 55) discuss the use of nicotine containing dextrose and magnesium hydroxide tablets. The subjects were instructed to keep the tablets in the mouth for some minutes before swallowing, in order to maximize contact with the buccal mucosa.
Several products based on the above mentioned patents are now marketed on an international scale. In addition, several nicotine lozenges are available as over-the-counter products in the U.K. xe2x80x9cResolutionxe2x80x9d lozenges, manufactured by Phoenix Pharmaceuticals and distributed by Ernest Jackson, contain 0.5 mg nicotine, together with the anti-oxidant vitamins A, C, and E. xe2x80x9cStoppersxe2x80x9d lozenges, distributed by Charwell Pharmaceuticals Ltd., contain 0.5 mg nicotine and are available in chocolate, orange and peppermint flavors.
There are, however, subjects who may have cravings for higher doses of nicotine than those acceptable in applications of prior art and subjects that may not experience a decrease in other withdrawal symptoms because of unsatisfactory nicotine absorption. Furthermore, it has to date been difficult to deliver nicotine in a profile mimicking the nicotine blood levels achieved by consistent smoking, to satisfy cravings for nicotine in people who are attempting to quit smoking, and thus, to provide greater protection against relapse than nicotine replacement therapies is possible with hitherto known. Thus, absorption of nicotine in the use of currently marketed products and as disclosed in prior art of nicotine replacement therapies is not satisfactorily resembling the use of tobacco products, in particular smoking. With chewing gum nicotine replacement therapy for smoking cessation blood peak levels of nicotine is reached after 30 min. with venous blood nicotine levels about ⅓ to ⅔ of the levels attained when smoking (Br. Med. J. 1976, 1, 1043). A smoker will usually reach peak blood levels of nicotine 5-10 min. after starting smoking. It is therefore desirable to provide improved compositions and methods which avoid the disadvantages of these conventional nicotine delivery devices and methods while providing an effective means for delivering nicotine for smoking cessation treatment, for reducing nicotine craving, and for treating other conditions responsive to nicotine therapy.
We have surprisingly found that a rapid buccal absorption of nicotine is achieved through the use of nicotine containing formulations based on heterogeneous apolar-polar components. No similar formulations have been disclosed hitherto. The present formulations do not contain polyethylen glycols.
Compositions for the therapeutic delivery of nicotine are provided. Said compositions comprising nicotine provide rapid transmucosal absorption of nicotine. The compositions are preferably used for therapeutic administration of nicotine. The compositions are, preferably, applicable to, but not restricted to the buccal administration route.
The meaning of xe2x80x9cdisintegrationxe2x80x9d as used in the description and in the claims denotes melting, solubilization, erosion or a combinatorial effect of these physical changes of the invention.
The meaning of xe2x80x9cmelting point rangexe2x80x9d as used in the description and in the claims refers to the gradual decrease of the amount of solid, semisolid or amorphous material, as opposed to liquid material, as the temperature is increased.
The meaning of increase in xe2x80x9cfrequencyxe2x80x9d, as measured as the heart beat frequency (rate), as an indirect measure of nicotine absorption is used in the description and in the claims as detailed by Armitage (xe2x80x9cBlood levels of nicotine and cotinine attained during smokingxe2x80x9d in: The Workshop on Nicotine, Nov. 11-13, 1974, Stockholm, Sweden) and Schievelbein (xe2x80x9cNicotine, Resorption and Fatexe2x80x9d in Intl. Encyclop. Pharmacol. Therapeut. 1984, 114, 1). These references show that a rapid increase in plasma nicotine levels is associated with an increase in arterial blood pressure and heart rate.
xe2x80x9cAdhesivenessxe2x80x9d is readily appreciated, by those skilled in the art, to be a consequence of the behavior of the formulation in question in the environment of the site of application with which it is striving to approach uniformity in the sense of thermodynamics and mass transport. Adhesiveness is achieved through the driving force to reach close apposition caused by the formulation""s thermodynamic degree of freedom followed by the establishment of non-covalent interaction to the surface or site of application.